Abu Dhabi, UAE, September 17, 2026
Insilico Medicine has announced a new milestone from its UAE-based AI drug discovery operations, highlighting the discovery of novel Bruton’s tyrosine kinase (BTK)-targeting PROTACs with potential applications in blood cancers. The research, published in the Journal of Medicinal Chemistry, describes lead compounds ISM-PR25 and ISM-PR44, which were developed using Insilico’s proprietary Chemistry42 generative AI platform. The compounds demonstrated potent BTK degradation activity, selectivity and oral bioavailability in preclinical studies. The work represents a further expansion of Insilico Medicine’s research capabilities in the UAE and adds to the company’s broader portfolio of AI-enabled drug discovery and targeted protein degradation programs.
AI Platform Supports Novel BTK PROTAC Discovery
BTK is an established therapeutic target in B-cell malignancies, including chronic lymphocytic leukemia and mantle cell lymphoma. While BTK inhibitors have transformed treatment for several blood cancers, resistance mutations can emerge during therapy and limit long-term treatment effectiveness. Insilico’s research explores proteolysis-targeting chimeras (PROTACs) as a different strategy for addressing BTK biology. Instead of simply inhibiting the activity of BTK, PROTAC molecules are designed to recruit the cell’s protein-degradation machinery and promote the elimination of the target protein. Researchers used Chemistry42, Insilico’s generative AI platform, to design two novel Cereblon-binding warheads, identified as ISM-WH1 and ISM-WH2. The team subsequently optimized molecular linkers and evaluated more than 40 compounds while balancing degradation potency, selectivity, cellular toxicity and pharmacokinetic properties. This multi-parameter approach ultimately led to the identification of ISM-PR25 and ISM-PR44 as lead compounds for further investigation.
Lead Compounds Show Potent Preclinical BTK Degradation
The two lead compounds demonstrated sub-nanomolar BTK degradation activity in malignant B cells. ISM-PR25 achieved a reported DC₅₀ of 0.04 nM, while ISM-PR44 demonstrated a DC₅₀ of 0.05 nM. DC₅₀ represents the concentration required to achieve 50% degradation of the target protein. The study also reported activity against both wild-type and mutated BTK while avoiding concomitant degradation of several off-target proteins, including IKZF1, IKZF3 and GSPT1. The compounds also demonstrated oral bioavailability in mice, reaching approximately 26% for ISM-PR25 and 29% for ISM-PR44. In pharmacodynamic studies, a single oral dose of 3 mg/kg reduced BTK levels in circulating mouse B cells. These findings provide preclinical evidence supporting additional investigation of the compounds as potential orally administered BTK degraders. However, ISM-PR25 and ISM-PR44 remain research-stage compounds, and their safety and efficacy in humans have not yet been established. The study also addresses an important challenge in PROTAC development: achieving sufficient potency while maintaining selectivity, pharmacokinetic properties and tolerability. Insilico reported that its novel Cereblon-binding warheads helped reduce off-target degradation associated with traditional thalidomide-derived approaches. The findings illustrate how AI-assisted molecular design can be combined with medicinal chemistry and experimental biology to optimize complex drug candidates.
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UAE Team Expands Local AI Drug Discovery
The BTK program builds on Insilico Medicine’s growing drug discovery presence in the United Arab Emirates. The company’s Abu Dhabi-based research operation has previously contributed to the discovery of ISM0387, a PRMT5 inhibitor described by Insilico as the first AI-driven innovative drug discovery milestone originating from the UAE. The company has established its Generative AI and Quantum Computing Research and Development Center at Masdar City and has developed research relationships with UAE academic institutions. The latest BTK research demonstrates how the UAE operation is contributing to programs involving targeted protein degradation and generative AI-enabled medicinal chemistry. For Insilico, the work forms part of a broader strategy integrating artificial intelligence, automation and experimental drug discovery across oncology, immunology, fibrosis, metabolic disease and other therapeutic areas.
While further preclinical optimization and eventual clinical studies will be necessary to determine the therapeutic potential of ISM-PR25 and ISM-PR44, the publication provides evidence of AI-supported discovery of selective, orally bioavailable BTK-targeting PROTAC leads. The research also highlights the expanding role of the UAE in Insilico Medicine’s global drug discovery network.
Source: Insilico Medicine press release
